Project Summary/Abstract Cannabis use disorder (CUD) is a significant public health concern. Cannabis is the most frequently used illicit substance in the United States, with 19.8 million users in 2013. 1 Among adolescents ages 18-21, 6.9% use cannabis daily. 2 Daily cannabis use rates in adolescents are the highest in 30 years and now surpass cigarette use. 2 In 2013, 4.2 million individuals met criteria for CUD 1, making it one of the most common psychiatric disorders. CUD is associated with physical and psychological conditions and decreased achievement 2-8; however, the impact of CUD on indices of brain integrity is unclear. A limited number of studies have used diffusion tensor imaging (DTI) to assess the white matter (WM) microstructure among individuals with CUD. CUD is associated with WM compromise 10-17, albeit inconsistently. 18,19 Similarly, CUD is related to neuropsychological deficits 25-30, yet there is variability among individuals with CUD. 31-34 Thus, despite rising rates of CUD among adolescents 2, the full effect of CUD on brain integrity remains unknown. As reduced WM integrity and cognitive deficits have significant implications for functioning and mental health 35, it is critical to elucidate the relationship between CUD and brain integrity. Factors that may explain the variability in CUD-related reductions in WM integrity and cognitive deficits merit attention. Conflicting findings may signify the presence of a sub-group of individuals who are at greater risk of CUD-related WM and cognitive deficits; however, this has yet to be determined. Early life stress (ELS) is putative factor that may help clarify the relationship between CUD and brain structure and function in adolescents. ELS is common among adolescents with CUD 37, 38, and is related to the development of CUD. 37-40 ELS is also a serious public health concern and the adverse impact of ELS on WM microstructure and cognitive functioning is well-documented. 42-53 As the brain is still developing in adolescents, it is imperative to understand the relationship between ELS and brain structure and function in adolescents with CUD. Yet, there is effectively no information regarding the co-occurrence of CUD and ELS on brain integrity in this population. The proposed study will be the first to examine the combined effects of CUD and ELS on measures of brain integrity in adolescents using DTI and neuropsychological tests. We will recruit two groups of adolescents with CUD (ages 18-21), 30 with previous ELS, 30 without ELS as well as a sample of 20 healthy adolescents without CUD and ELS exposure. All participants will undergo DTI neuroimaging and neuropsychological assessment. The proposed study will be the first to delineate a neuroimaging and cognitive phenotype for adolescents with CUD and ELS. Results from this study will advance our understanding of the mechanisms of variability that lead to decreased brain integrity in adolescents with CUD. These findings will generate valuable information that may be used to identify important intervention targets. The results will provide the foundation for a subsequent large-scale study focused on multimodal neuroimaging, CUD, and ELS.